This invention is related to percutaneous biological fluid sampling and analyte measurement devices and methods.
The detection of analytes in biological fluids is of ever increasing importance. Analyte detection assays find use in a variety of applications, including clinical laboratory testing, home testing, etc., where the results of such testing play a prominent role in the diagnosis and management of a variety of disease conditions. Common analytes of interest include glucose, e.g., for diabetes management, cholesterol, and the like.
A common technique for collecting a sample of blood for analyte determination is to pierce the skin at least into the subcutaneous layer to access the underlining blood vessels in order to produce localized bleeding on the body surface. The accessed blood is then collected into a small tube for delivery and analyzed by testing equipment, often in the form of a hand-held instrument having a reagent test strip onto which the blood sample is placed. The fingertip is the most frequently used site for this method of blood collection due to the large number of small blood vessels located therein. This method has the significant disadvantage of being very painful because subcutaneous tissue of the fingertip has a large concentration of nerve endings. It is not uncommon for patients who require frequent monitoring of an analyte to avoid having their blood sampled. With diabetics, for example, the failure to frequently measure their glucose level on a prescribed basis results in a lack of information necessary to properly control the level of glucose. Uncontrolled glucose levels can be very dangerous and even life-threatening. This technique of blood sampling also runs the risk of infection and the transmission of disease to the patient, particularly when done on a high-frequency basis. The problems with this technique are exacerbated by the fact that there is a limited amount of skin surface that can be used for the frequent sampling of blood without forming thick calluses.
To overcome the disadvantages of the above technique and others that are associated with a high degree of pain, certain analyte detection protocols and devices have been developed that use micro-needles or analogous structures to access the interstitial fluid within the skin. The micro-needles are penetrated into the skin to a depth less than the subcutaneous layer so as to minimize the pain felt by the patient. The interstitial fluid is then sampled and tested to determine the concentration of the target constituent. The concentration of a constituent within the interstitial fluid is representative of the concentration of that constituent in other bodily fluids, such as blood.
Conventional micro-needle sampling systems have a drawback in that, because the interstitial fluid inside the human body is at a negative pressure of about 6 mm/Hg, some kind of mechanical or vacuum means is often used in conjunction with the micro-piercing members.
For example, International Patent Application WO 99/27852 discloses the use of vacuum pressure and/or heat to increase the availability of interstitial fluid at the area of skin in which the vacuum or heat is applied. The vacuum pressure causes the portion of skin in the vicinity of the vacuum to become stretched and engorged with interstitial fluid, facilitating the extraction of fluid upon entry into the skin. Another method is disclosed wherein a localized heating element is positioned above the skin, causing interstitial fluid to flow more rapidly at that location, thereby allowing more interstitial fluid to be collected per given unit to time.
Still other detection devices have been developed which avoid penetration of the skin altogether. Instead the outermost layer of skin, called the stratum corneum, is xe2x80x9cdisruptedxe2x80x9d by a more passive means to provide access to or extraction of biological fluid within the skin. Such means includes the use of oscillation energy, the application of chemical reagents to the skin surface, etc. For example, International Patent Application WO 98/34541 discloses the use of an oscillation concentrator, such as a needle or wire, which is positioned at a distance from the skin surface and caused to vibrate by means of an electro-mechanical transducer. The needle is immersed in a receptacle containing a liquid medium placed in contact with the skin. The mechanical vibration of the needle is transferred to the liquid, creating hydrodynamic stress on the skin surface sufficient to disrupt the cellular structure of the stratum corneum. International Patent Applications WO 97/42888 and WO 98/00193 also disclose methods of interstitial fluid detection using ultrasonic vibration.
Thus, despite the work that has already been done in the area of analyte testing, there is a continued interest in the identification of new analyte detection methods that more readily meet the needs of the relevant market. Of particular interest would be the development of a minimally invasive analyte detection system that is practical, manufacturable, accurate and easy to use, as well as safe and efficacious.
Relevant Literature
U.S. Pat. Nos. of interest include: 5,582,184, 5,746,217, 5,820,570, 5,942,102, 6,091,975 and 6,162,611. Other patent documents and publications of interest include: WO 97/00441, WO 97/42888, WO 98/00193 WO 98/34541, WO 99/13336, WO 99/27852, WO 99/64580, WO 00/35530, WO 00/57177 and WO 00/74765A1.
Minimally invasive biological fluid sampling and analyte measurement devices and systems, as well as methods for using the same, are provided.
Generally, the subject devices of the present invention include an electrochemical cell having spaced-apart outer and inner electrodes for measuring the concentration of analyte within the biological fluid. The outer electrode has a chamber-defining configuration having an open distal end and at least a partially open proximal end. More specifically and preferably, the outer electrode has a continuous wall configuration which defines an interior lumen or chamber having a length. The distal edge of the wall defines a skin-contacting surface or pressure surface. In a preferred embodiment, the outer electrode has a cylindrical configuration defining an annular skin-contacting surface at the distal end such that, when operatively applied to the skin, the annular surface acts as a pressure ring on the skin surface.
The inner electrode has a solid, elongated configuration having a length which is positioned co-axially within the lumen or chamber of the outer electrode. The inner electrode has a proximal end and a distal end configured to pierce a skin surface to provide access to biological fluid. The length of the inner electrode relative to the outer electrode is a factor in determining the depth of penetration of the inner electrode. The outer and inner electrodes may be configured such that their respective distal ends are even with each other, or they may have different distally extending lengths.
The spacing between the electrodes defines a reaction chamber or zone within the electrochemical cell. This spacing is sufficiently narrow to exert a capillary force on the accessed biological fluid at it is open distal end thereby wicking it into the reaction chamber. The electrochemical cell of the present invention may further include an insulator positioned within the reaction chamber in sealed engagement at the proximal end of the electrochemical cell. Collectively, these components define a sensor device having a cup-like configuration.
The sensor device of the present invention is employed to make an electrochemical measurement of an analyte in a sample of biological fluid that has been accessed by the skin-piercing, inner electrode and then transported (by a capillary action) into the electrochemical cell. The electrochemical cell may be designed to provide a coulometric, amperometric or potentiometric measurement. Also, a plurality of the sensor devices of the present invention may be provided in the form of an array. The plurality of sensor devices may have identical configurations, electrode lengths and reagent types, or may have different configurations, electrode lengths and reagent types for accessing different layers of skin and testing different analytes.
An exemplary method of the subject invention involves using at least one subject sensor device just described. The distal end of the device is positioned or cupped over an area of the patient""s skin such that the skin-contacting surface of the outer electrode is flush with the skin surface. Slight pressure is exerted on the proximal end of the sensor device, causing the skin-contacting surface to exert a pressure on the contacted skin and thereby causing the covered portion of skin to bulge upward into the spacing between the electrodes. The skin-piercing inner electrode is then able to atraumatically penetrate the skin to a selected depth, preferably to a depth that avoids contacting nerve endings and blood vessels. Next, the sample of biological fluid present at the open distal end of the device is then wicked, by means of a capillary force, into the electrochemical cell. An electrochemical measurement is then made between the electrodes which provides an electrical signal representative of the concentration of the target constituent(s) within the sample. The concentration of the constituent(s) in the patient""s blood is then derived from the obtained electrical signal.
A redox reagent system or material may be used within the electrochemical cell to facilitate targeting the analyte(s) of interest. The particular redox reagent material used is selected based on the analyte targeted for measurement.
The subject sensor devices may function as a part of an analyte sensing system that includes a means for controlling the sensor device. Specifically, a control unit is provided in which the control means is electrically coupled with the sensor device and functions to generate and send input signals to the electrochemical cell and to receive output signals from the cell. These functions, among others, are performed by a software algorithm programmed within the control unit that automatically calculates and determines the concentration of the target analyte in the biological sample upon receipt of an output signal from the electrochemical cell. The control unit may further include a display unit for displaying a numerical value representing the analyte concentration.
In operation, one of the electrodes of the electrochemical cell is used as the reference electrode by which an input reference signal is provided to the sensor from a signal generating means. Preferably, the inner electrode functions as a reference electrode for receiving an electrical signal from a signal-generating source, e.g., the control unit. The outer electrode then functions as a working electrode that provides an output signal from the electrochemical cell to a signal-receiving means, e.g., the control unit. This output signal represents the concentration of the target analyte within the sampled fluid.
An exemplary method of the subject invention involves using at least one subject sensor device. The sensor device is positioned over a target area of skin, and with sufficient pressure, the inner electrode/lancing member is caused to penetrate the surface of the skin to a selected depth, preferably to a depth that avoids contacting nerve endings and blood vessels. Next, the sample of biological fluid present at the open distal end of the sensor device is then wicked into the spacing or reaction zone between the inner and outer electrodes by capillary force. An electrochemical measurement is then made between the working and reference electrodes that provides an electrical signal that is representative of the concentration the constituent in the sample. The concentration of the constituent(s) in the patient""s blood is then derived from the obtained electrical signal. A numerical value representing this concentration may then be displayed on a display unit. A software algorithm that is part of the device, e.g., programmed into a control unit present in the device, may be employed to determine the signal levels transmitted by the control unit to the cell and for deriving the concentration level of the target analyte.